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    Summary
    EudraCT Number:2014-005068-13
    Sponsor's Protocol Code Number:I4T-MC-JVDE
    National Competent Authority:Austria - BASG
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2015-04-28
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedAustria - BASG
    A.2EudraCT number2014-005068-13
    A.3Full title of the trial
    Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of Ramucirumab and Best Supportive Care (BSC) Versus Placebo and BSC as Second-Line Treatment in Patients With Hepatocellular Carcinoma and Elevated Baseline Alpha-Fetoprotein (AFP) Following First-Line Therapy With Sorafenib
    Eine randomisierte, doppel-blind, Placebo-kontrollierte, Phase 3 Studie von Ramucirumab und bestmöglicher unterstützender Behandlungsmaßnahmen versus Placebo und bestmöglicher unterstützender Behandlungsmaßnahmen als zweit – Linien Therapie an Patienten mit Hepatozellulärem Karzinom , erhöhtem Alpha – Feto Protein Grundwert nach einer erst – Linien Therapie mit Sorafenib
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study of Ramucirumab (LY3009806) and best supportive care in Participants with Hepatic Cancer
    Eine Studie von Ramucirumab und bestmöglicher unterstützender Behandlungsmaßnahmen bei Teilnehmern mit Leber Krebs
    A.4.1Sponsor's protocol code numberI4T-MC-JVDE
    A.5.3WHO Universal Trial Reference Number (UTRN)U1111-1165-1891
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorEli Lilly and Company
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportEli Lilly and Company
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationEli Lilly and Company
    B.5.2Functional name of contact pointClinical Trial Registry Office
    B.5.3 Address:
    B.5.3.1Street AddressLilly Corporate Center, DC 1526
    B.5.3.2Town/ cityIndianapolis
    B.5.3.3Post code46285
    B.5.3.4CountryUnited States
    B.5.6E-mailEU_Lilly_Clinical_Trials@lilly.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Cyramza
    D.2.1.1.2Name of the Marketing Authorisation holderEli Lilly NederlandB.V.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRamucirumab
    D.3.9.1CAS number 947687-13-0
    D.3.9.3Other descriptive nameRAMUCIRUMAB
    D.3.9.4EV Substance CodeSUB32795
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboConcentrate for solution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Hepatocellular Carcinoma
    E.1.1.1Medical condition in easily understood language
    Hepatic Cancer
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10019828
    E.1.2Term Hepatocellular carcinoma non-resectable
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective is to compare overall survival (OS) for ramucirumab versus placebo in patients with advanced HCC after intolerance or progression on prior sorafenib treatment

    The primary objective of the open-label, nonrandomized, expansion cohort (Open-label Cohort) is to evaluate the safety profile of ramucirumab in patients with advanced HCC after prior systemic therapy other than prior sorafenib.
    E.2.2Secondary objectives of the trial
    The secondary objectives of the study are to evaluate:
    • Progression-free survival (PFS)
    • Time to radiographic progression (TTP)
    • Objective response rate (ORR)
    • safety profile of ramucirumab
    • ramucirumab pharmacokinetics (PK)
    • Immunogenicity of ramucirumab
    • Time to deterioration in Functional Assessment of Cancer Therapy (FACT) Hepatobiliary Symptom Index-8 (FHSI-8)
    • Time to deterioration in Eastern Cooperative Oncology Group performance status (ECOG PS)
    • Other patient-reported outcome (PRO) measures of disease-specific symptoms and health related quality of life


    The secondary objectives of the Open-label Cohort are to evaluate:
    • overall survival (OS)
    • progression-free survival (PFS)
    • time to radiographic progression
    • objective response rate
    • ramucirumab pharmacokinetics
    • immunogenicity of ramucirumab
    • patient-reported outcome (PRO) measures of disease-specific symptoms and health-related quality of life
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    [1] The patient has a diagnosis of HCC based on either:
    a. histopathologic or cytologic findings
    b. in the absence of histologic confirmation, a diagnosis of cirrhosis and HCC with classical imaging characteristics (that is, at least a 3-phase liver protocol CT or MRI and a lesion that demonstrates arterial hyperenhancement and washes out in the venous phase).
    [2] The patient received sorafenib treatment for at least 14 days and discontinued sorafenib treatment 14 days prior to randomization.
    [3] The patient experienced radiographically confirmed disease progression during or after discontinuation of sorafenib therapy or discontinued sorafenib treatment because of intolerance despite appropriate sorafenib management and supportive care.
    [4] The patient received sorafenib as the only systemic therapeutic intervention for advanced HCC.
    [5] The patient has 1 measurable lesion per Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 (Eisenhauer et al. 2009) that has not been previously treated with locoregional therapy.
    [6] The patient is 18 years of age or of an age acceptable according to local regulations, whichever is older.
    [7] The patient has a Child-Pugh score of <7 (Child-Pugh Class A only).
    [8] The patient has Barcelona Clinic Liver Cancer (BCLC) Stage C disease or BCLC Stage B disease not amenable to locoregional therapy or refractory to locoregional therapy.
    [9] The patient has a baseline AFP 400 ng/mL, as determined by local laboratory testing.

    Inclusion criteria for the Open-label Cohort are:
    Protocol Inclusion Criteria [2], [3], and [4] do not apply to the Open-
    Label Cohort. All other inclusion criteria apply to the Open-Label Cohort.
    The following additional Inclusion Criterion apply to the Open-Label
    Cohort:
    -The patient received 1 prior systemic therapy regimen, excluding prior sorafenib, for the treatment of HCC.
    -The patient discontinued from prior systemic therapy 14 days prior to enrollment.
    -The patient experienced radiographically confirmed disease progression during or after discontinuation of prior systemic therapy or discontinued
    prior systemic treatment because of intolerance, despite appropriate management and supportive care.
    E.4Principal exclusion criteria
    [17] The patient has fibrolamellar carcinoma or mixed hepatocellular cholangiocarcinoma.
    [18] The patient had a previous or has concurrent malignancy. Patients with carcinoma in situ of any origin and patients with prior malignancies who are in remission and whose likelihood of recurrence is very low, as judged by the investigator, may be eligible for this study in consultation with and approval by the Lilly CRP.
    [19] The patient has previously documented brain metastases, leptomeningeal disease, or uncontrolled spinal cord compression.
    [20] The patient has a history of or current hepatic encephalopathy (any grade) or clinically meaningful ascites. Clinically meaningful ascites is defined as CTCAE Grade >1 ascites resulting from cirrhosis. Patients who have been on a stable medical regimen (for 3 months) to manage ascites are eligible if they show no evidence of ascites on clinical exam that would require further intervention.
    [21] The patient has ongoing or recent (6 months prior to randomization) hepatorenal syndrome.
    [22] The patient had a prior liver transplant.
    [23] The patient received any previous systemic therapy with VEGF inhibitors or VEGF-Receptor inhibitors (including investigational agents) other than sorafenib for treatment of HCC.
    [24] The patient received any hepatic locoregional therapy (including radiation, surgery, hepatic arterial embolization, chemoembolization, radiofrequency ablation, cryoablation, or percutaneous ethanol injection) following sorafenib or within 28 days prior to randomization. Use of locoregional therapy prior to sorafenib is allowed.
    [25] The patient received radiation to any nonhepatic (for example, bone) site within 14 days prior to randomization. Prior radiation to >25% total bone marrow is not allowed.

    Exclusion criteria for the Open-label Cohort are:
    Protocol Exclusion Criteria [23] and [24] do not apply to the Open-Label Cohort. All other exclusion criteria apply to the Open-Label Cohort.
    The following additional Exclusion Criterion applies to the Open-Label Cohort:
    -The patient received any hepatic locoregional therapy (including radiation, surgery, hepatic arterial embolization, chemoembolization, radiofrequency ablation, cryoablation, or percutaneous ethanol injection) following prior systemic therapy or within 28 days prior to randomization. Use of locoregional therapy prior to completion of
    systemic therapy is allowed.
    The following additional Exclusion Criteria apply to patients who received prior immunotherapy (for example, inhibitors of programmed death 1, programmed death ligand 1, and/or cytotoxic T lymphocyte antigen 4):
    -The patient is experiencing, or has experienced, any of the following:
    a. any clinically significant Grade 3 immune-related adverse event (irAE)
    b. any grade neurologic or ocular irAE
    c. any grade immune-related pneumonitis, cardiomyopathy, or hepatitis
    -At the time of study enrollment, the patient requires steroids or other immunosuppressive agents (such as anti-thymocyte globulin [ATG] or cyclosporine).
    E.5 End points
    E.5.1Primary end point(s)
    Compare ramucirumab versus placebo in terms of OS in patients with advanced HCC after intolerance or progression on prior sorafenib

    Primary end point of the Open-label Cohort is to evaluate the safety profile of ramucirumab in patients with advanced HCC after prior systemic therapy other than prior sorafenib.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary analysis will be performed after approximately 221 deaths have been observed

    The primary endpoint for Open-label Cohort will be assessed after all patients enrolled in the Open-Label Cohort have completed at least 3 cycles of ramucirumab or discontinued for any reason.
    E.5.2Secondary end point(s)
    The secondary objectives of the study are to evaluate: progression-free survival, time to radiographic progression, objective response rate (ORR), safety profile of ramucirumab, ramucirumab pharmacokinetics, immunogenicity of ramucirumab, time to deterioration in Eastern Cooperative Group performance status (ECOG PS), time to deterioration in Functional Assessment of Cancer Therapy (FACT) Hepatobiliary Symptom Index-8 (FHSI-8) and other patient-reported outcome measures of disease-specific symptoms and health-related quality of life.

    The secondary objectives of the Open-label Cohort are to evaluate:
    overall survival (OS); progression-free survival (PFS); time to radiographic progression; objective response rate; ramucirumab pharmacokinetics; immunogenicity of ramucirumab; patient-reported outcome (PRO) measures of disease-specific symptoms and healthrelated quality of life
    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary endpoints will be analyzed at the same time as OS and at the same level of significance.
    2 safety interim analyses are planned to be performed when approximately 50 and 150 patients have received 3 cycles of study treatment, died, or discontinued study treatment. Thereafter, safety review will be conducted twice annually, or as requested by the IDMC

    Secondary end points for the Open-label Cohort will be assessed after all patients enrolled in the Open-Label Cohort have completed at least 3 cycles of ramucirumab or discontinued for any reason.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Immunogenicity, Health Outcome
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA51
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Austria
    Belgium
    Brazil
    Canada
    China
    Czech Republic
    France
    Germany
    Hong Kong
    Israel
    Italy
    Japan
    Korea, Republic of
    Poland
    Spain
    Switzerland
    Taiwan
    United Kingdom
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months10
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months10
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 170
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 153
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state2
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 148
    F.4.2.2In the whole clinical trial 323
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-06-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-05-15
    P. End of Trial
    P.End of Trial StatusOngoing
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